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SUMMARY

These revised recommendations of the Immunization Practices Advisory
Committee (ACIP) on rabies prevention update the previous recommendations
(MMWR 1980;29:65-72,277-80) to reflect the current status of rabies and
antirabies biologics in the United States. For assistance on problems or
questions about rabies prophylaxis, call local or state health departments.*

INTRODUCTION

Although rabies rarely affects humans in the United States, every year,
approximately 25,000 persons receive rabies prophylaxis. Appropriate
managment of those who may have been exposed to rabies infection depends on
the interpretation of the risk of infection and the efficacy and risk of
prophylactic treatment. All available methods of systemic prophylactic
treatment are complicated by instances of adverse reactions. These are rarely
severe. Decisions on management must be made immediately; the longer
treatment is postponed, the less likely it is to be effective.

Data on the efficacy of active and passive immunization after rabies
exposure have come from both human and animal studies. Evidence from
laboratory and field experience in many areas of the world indicates that
postexposure prophylaxis combining local wound treatment, vaccine, and rabies
immune globulin, is uniformly effective when appropriately used. However,
rabies has occasionally developed in humans who had received postexposure
antirabies prophylaxis with vaccine alone.

In the United States, rabies in humans has decreased from an average of
22 cases per year in 1946-1950 to zero to five cases per year since 1960. The
number of rabies cases among domestic animals has decreased similarly. In
1946, more than 8,000 rabies cases were reported among dogs; 153 cases were
reported in 1982. Thus, the likelihood of human exposure to rabies in
domestic animals has decreased greatly, although bites by dogs and cats
continue to be the principal reasons given for antirabies treatments.

The disease in wildlife--especially skunks, foxes, raccoons, and bats--
has become more prevalent in recent years, accounting for approximately 85%
of all reported cases of animal rabies every year since 1976. Wild animals
now constitute the most important potential source of infection for both
humans and domestic animals in the United States. Rabies among animals is
present throughout the United States; only Hawaii remains consistently
rabies-free.

Four of the six rabies fatalities in U.S. citizens occurring between 1980
and 1983 were related to exposure to rabid dogs outside the United States. In
much of the world, including most of Asia and all of Africa and Latin
America, the dog remains the major source of human exposure.

RABIES IMMUNIZING PRODUCTS

There are two types of immunizing products: (1) vaccines that induce an
active immune response, which requires about 7-10 days to develop but may
persist for as long as a year or more, and (2) globulins that provide rapid
passive immune protection, which persists for a short period of time, with a
half-life of about 21 days. Both types of products should be used concur-
rently for rabies postexposure prophylaxis.

Vaccines for Use in the United States

Human diploid cell rabies vaccine (HDCV)**: HDCV is an inactivated virus
vaccine prepared from fixed rabies virus grown in WI-38 or MRC-5 human
diploid cell culture. The vaccine grown on WI-38 cells and developed in the
United States is inactivated with tri-n-butyl phosphate and B-propiolactone
(Wyeth Laboratories' WYVAC(R)), while that grown in MRC-5 cells and developed
in Europe is inactivated with B-propiolactone (Merieux Institute's RABIES
VACCINE(R)). Both vaccines are supplied as 1.0 ml, single-dose vials of
lyophilized vaccine with accompanying diluent.

Antirabies Serum, Equine (ARS): ANTIRABIES SERUM(R) (Sclavo) is a
refined, concentrated serum obtained from hyperimmunized horses. Neutralizing
antibody content is standardized to contain 1,000 IU per vial. Volume is
adjusted by the manufacturer on the basis of antibody potency in each lot.
Currently, a 1,000-IU vial contains approximately 5 ml.

RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS

Both types of HDCV rabies vaccines are considered equally efficacious and
safe when used as indicated on the labels. Only the Merieux Institute vaccine
has been evaluated by the intradermal (ID) dose/route for preexposure immunization. No data are available on ID use with the Wyeth Laboratories vaccine.
RIG is preferred over ARS, because the latter has a much higher risk of
adverse reactions.

Vaccines

The effectiveness of rabies vaccines is measured by their ability to
protect persons exposed to rabies and to induce antibodies to rabies virus.
HDCV has been used concurrently with RIG or ARS to treat 45 persons bitten by
rabid dogs or wolves in Iran, 31 persons bitten by a variety of rabid animals
in Germany, and 511 persons bitten by a variety of rabid animals in the
United States. In these studies, no person contracted rabies after receiving
HDCV in combination with RIG.

All persons treated with RIG and five 1.0-ml intramuscular (IM) doses of
HDCV and tested have developed a rabies antibody titer. The definition of a
minimally acceptable antibody titer varies between laboratories and is
influenced by the type of test conducted. CDC currently specifies a 1:5 titer
by the rapid fluorescent-focus inhibition test (RFFIT) as acceptable. The
World Health Organization (WHO) specifies a titer of 0.5 I.U.

Serious adverse reactions associated with rabies vaccines include
systemic, anaphylactic, and neuroparalytic reactions. Serious adverse
reactions occur at lower rates in the HDCV vaccine than with previously
available types of rabies vaccine.

Globulins

RIG and ARS are both effective; however, ARS causes serum sickness in
over 40% of adult recipients. RIG rarely causes adverse reactions and should
be the product of choice when available.

RATIONALE OF TREATMENT

Physicians must evaluate each possible rabies exposure. Local or state
public health officials should be consulted if questions arise about the need
for prophylaxis.

In the United States, the following factors should be considered before
specific antirabies treatment is initiated:

Species of Biting Animal

Carnivorous wild animals (especially skunks, raccoons, foxes, coyotes,
and bobcats) and bats are the animals most commonly infected with rabies and
have caused most of the indigenous cases of human rabies in the United States
since 1960. Unless an animal is tested and shown not to be rabid, postexposure prophylaxis should be initiated upon bite or nonbite exposure to the
animals. (See definition in "Type of Exposure" below.) If treatment has been
initiated and subsequent testing in a competent laboratory shows the exposing
animal is not rabid, treatment can be discontinued.

The likelihood that a domestic dog or cat is infected with rabies varies
from region to region; hence, the need for postexposure prophylaxis also
varies.

Rodents (such as squirrels, hamsters, guinea pigs, gerbils, chipmunks,
rats, and mice) and lagomorphs (including rabbits and hares) are rarely found
to be infected with rabies and have not been known to cause human rabies in
the United States. In these cases, the state or local health department
should be consulted before a decision is made to initiate postexposure
antirabies prophylaxis.

Circumstances of Biting Incident

An unprovoked attack is more likely than a provoked attack to indicate
the animal is rabid. Bites inflicted on a person attempting to feed or handle
an apparently healthy animal should generally be regarded as provoked.

Type of Exposure

Rabies is transmitted by introducing the virus into open cuts or wounds
in skin or via mucous membranes. The likelihood of rabies infection varies
with the nature and extent of exposure. Two categories of exposure should be
considered.

Bite: Any penetration of the skin by teeth.

Nonbite: Scratches, abrasions, open wounds, or mucous membranes contam-
inated with saliva or other potentially infectious material, such as brain
tissue, from a rabid animal. Casual contact, such as petting a rabid anima
(without a bite or nonbite exposure as described above), does not constitu
an exposure and is not an indication for prophylaxis. There have been two
instances of airborne rabies acquired in laboratories and two probable
airborne rabies cases acquired in a bat-infested cave in Texas.

The only documented cases of rabies from human-to-human transmission
occurred in four patients in the United States and overseas who received
corneas transplanted from persons who died of rabies undiagnosed at the time
of death. Stringent guidelines for acceptance of donor corneas should reduce
this risk.

Bite and nonbite exposures from humans with rabies theoretically could
transmit rabies, although no cases of rabies acquired this way have been
documented. Each potential exposure to human rabies should be carefully
evaluated to minimize unnecessary rabies prophylaxis.

MANAGEMENT OF BITING ANIMALS

A healthy domestic dog or cat that bites a person should be confined and
observed for 10 days and evaluated by a veterinarian at the first sign of
illness during confinement or before release. Any illness in the animal
should be reported immediately to the local health department. If signs
suggestive of rabies develop, the animal should be humanely killed and its
head removed and shipped, under refrigeration, for examination by a qualified
laboratory designated by the local or state health department. Any stray or
unwanted dog or cat that bites a person should be killed immediately and the
head submitted, as described above, for rabies examination.

Signs of rabies in wild animals cannot be interpreted reliably; therefore, any wild animal that bites or scratches a person should be killed at
once (without unnecessary damage to the head) and the brain submitted, as
described above, for examination for evidence of rabies. If the brain is
negative by fluorescent-antibody examination for rabies, the saliva can be
assumed to contain no virus, and the bitten person need not be treated. If
the biting animal is a particularly rare or valuable specimen and the risk of
rabies small, consideration may be given to initiating postexposure treatment
to the bitten person and delaying killing the animal for rabies testing.

POSTEXPOSURE PROPHYLAXIS

The essential components of rabies postexposure prophylaxis are local
treatment of wounds and immunization, including administration, in most
instances, of both globulin and vaccine (Tables 1 and 2).

Local Treatment of Wounds

Immediate and thorough washing of all bite wounds and scratches with soap
and water is perhaps the most effective measure for preventing rabies. In
experimental animals, simple local wound cleansing has been shown to reduce
markedly the likelihood of rabies.

Tetanus prophylaxis and measures to control bacterial infection should be
given as indicated.

Immunization

Postexposure antirabies immunization should always include administration
of both antibody (preferably RIG) and vaccine, with one exception: persons
who have been previously immunized with the recommended preexposure or
postexposure regimens with HDCV or who have been immunized with other types
of vaccines and have a history of documented adequate rabies antibody titer
(See "RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS") should receive
only vaccine. The combination of globulin and vaccine is recommended for both
bite exposures and nonbite exposures (as described under "RATIONALE OF
TREATMENT"), regardless of the interval between exposure and treatment. The
sooner treatment is begun after exposure, the better. However, there have
been instances in which the decision to begin treatment was made as late as
6 months or longer after the exposure due to delay in recognition that an
exposure had occurred.

HDCV: HDCV is the only type of vaccine currently available in the United
States and should be administered in conjunction with RIG at the beginning of
postexposure therapy, as described below. In 1977, WHO established a recommendation for six IM doses of HDCV based on studies in Germany and Iran of a
regimen of RIG or ARS and six doses of HDCV. When used in this way, the
vaccine was safe and effective in protecting 76 persons bitten by proven
rabid animals. The vaccine also induced an excellent antibody response in all
recipients. Studies conducted by CDC in the United States have shown that a
regimen of one dose of RIG and five doses of HDCV was safe and induced an
excellent antibody response in all recipients. Of 511 persons bitten by
proven rabid animals and so treated, none developed rabies.

Five 1-ml doses of HDCV should be given intramuscularly (for example, in
the deltoid region). Other routes of administration, such as the ID route,
have not been adequately evaluated for postexposure prophylaxis and should
not be used. The first dose should be given as soon as possible after
exposure; an additional dose should be given on days 3, 7, 14, and 28 after
the first dose. (WHO currently recommends a sixth dose 90 days after the
first dose.) Because the antibody response following the recommended
vaccination regimen with HDCV has been so satisfactory, routine postvaccination serologic testing is not recommended. In unusual instances, as when
the patient is known to be immunosuppressed, serologic testing is indicated.
Contact state health department or CDC for recommendations.

RIG (or ARS if RIG is not available): RIG is administered only once, at
the beginning of antirabies prophylaxis, to provide immediate antibodies
until the patient responds to HDCV by active production of antibodies. If RIG
was not given when vaccination was begun, it can be given up to the eighth
day after the first dose of vaccine was given. From about the eighth day on,
RIG is not indicated, since an antibody response to the vaccine is presumed
to have occurred. The recommended dose of RIG is 20 IU/kg or approximately 9
IU/lb of body weight. (When ARS must be used, the recommended dose is 40
IU/kg, approximately 18 IU/lb or 1,000 IU/55 lb body weight.) If anatomically
feasible, up to half the dose of RIG should be thoroughly infiltrated in the
area around the wound, the rest should be administered intramuscularly.
Because RIG may partially suppress active production of antibody, no more
than the recommended dose of RIG should be given.

TREATMENT OUTSIDE THE UNITED STATES

If postexposure is begun outside the United States with locally produced
biologics, it may be desirable to provide additional treatment when the
patient reaches the United States. State health departments should be
contacted for specific advice in such cases.

PREEXPOSURE IMMUNIZATION

Preexposure immunization may be offered to persons in high-risk groups,
such as veterinarians, animal handlers, certain laboratory workers, and
persons spending time (e.g., 1 month or more) in foreign countries where
rabies is a constant threat. Persons whose vocational or avocational pursuits
bring them into contact with potentially rabid dogs, cats, foxes, skunks,
bats, or other species at risk of having rabies should also be considered for
preexposure prophylaxis.

Preexposure prophylaxis is given for several reasons. First, it may
provide protection to persons with inapparent exposures to rabies. Second, it
may protect persons whose postexposure therapy might be expected to be
delayed. Finally, although it does not eliminate the need for additional
therapy after a rabies exposure, it simplifies therapy by eliminating the
need for globulin and decreasing the number of doses of vaccine needed. This
is of particular importance for persons at high risk of being exposed in
countries where the available rabies immunizing products may carry a higher
risk of adverse reactions.

Preexposure immunization does not eliminate the need for prompt postexposure prophylaxis following an exposure; it only reduces the postexposure
regimen.

Human Diploid Cell Rabies Vaccine

Three 1.0 ml injections of HDCV should be given intramuscularly (for
example, in the deltoid area), one on each of days O, 7, and 28. In a study
in the United States, more than 1,000 persons received HDCV according to this
regimen; antibody was demonstrated in the sera of all subjects when tested by
the RFFIT. Other studies have produced comparable results. Because the anti-
body response following the recommended vaccination regimen with HDCV has
been so satisfactory, routine postvaccination serology is not recommended.

Booster Doses of Vaccine

Persons who work with live rabies virus in research laboratories or
vaccine production facilities and are at risk of inapparent exposure should
have the rabies antibody titer of their serum determined every 6 months;
booster doses of vaccine should be given, as needed, to maintain an adequate
titer (See "RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS"). Other
laboratory workers, such as those doing rabies diagnostic tests, spelunkers,
and those veterinarians, animal control and wildlife officers in areas where
animal rabies is epizootic should have boosters every 2 years or have their
serum tested for rabies antibody every 2 years and, if the titer is inadequate, have a booster dose. Veterinarians and animal control and wildlife
officers, if working in areas of low rabies endemicity, do not require routine booster doses of HDCV after completion of primary preexposure immunization (Table 2).

Postexposure Therapy of Previously Immunized Persons

When an immunized person who was vaccinated by the recommended regimen
with HDCV or who had previously demonstrated rabies antibody is exposed to
rabies, that person should receive two IM doses (1.0 ml each) of HDCV, one
immediately and one 3 days later. RIG should not be given in these cases. If
the immune status of a previously vaccinated person who did not receive the
recommended HDCV regimen is not known, full primary postexposure antirabies
treatment (RIG plus five doses of HDCV) may be necessary. In such cases, if
antibody can be demonstrated in a serum sample collected before vaccine is
given, treatment can be discontinued after at least two doses of HDCV.

Intradermal Use of HDCV

HDCV produced by the Merieux Institute has been used for preexposure
immunization in a regimen of three 0.1 ml doses given ID in the lateral
aspect of the upper arm over the deltoid area, one dose each on days O, 7,
and 28. Experience gained with over 2,000 persons vaccinated in the United
States by the ID route has shown that antibody was produced in all recipients, although the mean response was somewhat lower and may be of shorter
duration than with comparable IM immunization. Antibody response in some
groups vaccinated outside the United States has been found to be inadequate
for reasons not yet determined.

Current data provide a sufficient basis to recommend the 0.1 ml ID
dose/route as an alternative to the 1.0 ml IM dose/route for preexposure
immunization in the United States. Postvaccination serology is not necessary
following ID (or IM) immunization, except for persons suspected of being
immunosuppressed. The manufacturer has not yet met the packaging and labeling
requirements necessary to obtain approval by the U.S. Food and Drug Adminis-
tration for the ID route. Since the 1.0-ml vial presently available is
intended for IM use and contains no preservatives, the reconstituted vaccine
must be used immediately. Data on ID immunization are not available for Wyeth
Laboratories' vaccine, and it should not be used for ID vaccination.

ACCIDENTAL INOCULATION WITH MODIFIED LIVE RABIES VIRUS

Individuals may be accidentally exposed to attenuated rabies virus while
administering modified live rabies virus (MLV) vaccines to animals. While
there have been no reported human rabies cases resulting from exposure to
needlesticks or sprays with licensed MLV vaccines, vaccine-induced rabies has
been observed in animals given MLV vaccines. Absolute assurance of a lack of
risk for humans, therefore, cannot be given. The best evidence for a low
risk, however, is the absence of recognized cases of vaccine-associated
disease in humans despite frequent accidental exposures.

Currently available MLV animal vaccines are made with one of two attenuated strains of rabies virus: high egg passage (HEP) Flury strain or Street
Alabama Dufferin (SAD) strain. The HEP Flury and SAD virus strains have been
used in animal vaccines for over 10 years without evidence of associated
disease in humans; therefore, postexposure treatment is not recommended
following exposure to these types of vaccine by needlesticks or sprays.

Because the data are insufficient to assess the true risk associated with
any of the MLV vaccines, preexposure immunization, and periodic boosters are
recommended for all persons dealing with potentially rabid animals or
frequently handling animal rabies vaccines.

ADVERSE REACTIONS

Human Diploid Cell Rabies Vaccine

Reactions after vaccination with HDCV are less common than with
previously available vaccines. In a study using five doses of HDCV, local
reactions, such as pain, erythema, and swelling or itching at the injection
site, were reported in about 25% of recipients of HDCV, and mild systemic
reactions, such as headache, nausea, abdominal pain, muscle aches, and dizzi-
ness were reported in about 20% of recipients. Two cases of neurologic
illness resembling Guillain-Barre syndrome that resolved without sequelae in
12 weeks, and a focal subacute central nervous system disorder temporally
associated with HDCV vaccine, have been reported.

Recently, a significant increase has been noted in "immune complex-like"
reactions in persons receiving booster doses of HDCV. The illness, charac-
terized by onset 2-21 days postbooster, presents with a generalized urticaria
and may also include arthralgia, arthritis, angioedema, nausea, vomiting,
fever, and malaise. In no cases were the illnesses life-threatening.
Preliminary data suggest this "immune complex-like" illness may occur in up
to 6% of persons receiving booster vaccines and much less frequently in
persons receiving primary immunization. Additional experience with this
vaccine is needed to define more clearly the risk of these adverse reactions.
Vaccines in Other Countries

Many developing countries use inactivated nerve tissue vaccines (NTV) or
inactivated suckling mouse brain vaccine (SMBV). NTV is reported to provoke
neuroparalytic reactions at a rate of about 1/2,000 vaccinees; the rate for
SMBV is about 1/8,000.

Rabies Immune Globulin, Human

Local pain and low-grade fever may follow receipt of RIG. Although not
reported specifically for RIG, angioneurotic edema, nephrotic syndrome, and
anaphylaxis have been reported after injection of immune serum globulin
(ISG). These reactions occur so rarely that the causal relationship between
ISG and these reactions is not clear.

Antirabies Serum, Equine

ARS produces serum sickness in at least 40% of adult recipients; reaction
rates for children are lower. Anaphylactic reactions may occur. When RIG is
not available, and ARS must be used, the patient should be tested for
sensitivity to equine serum. (See package circular for details.)

Because adverse reactions are associated more frequently with ARS than
with RIG, and ARS might sensitize recipients to equine protein, ARS should be
used only when RIG cannot be obtained.

Management of Adverse Reactions

Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine.
Usually such reactions can be successfully managed with anti-inflammatory and
antipyretic agents (aspirin, for example).

When a person with a history of hypersensitivity must be given rabies
vaccines, antihistamines may be given; epinephrine should be readily available to counteract anaphylactic reactions, and the person should be carefully
observed immediately after immunization.

Serious systemic anaphylactic or neuroparalytic reactions occurring
during the administration of rabies vaccines pose a serious dilemma for the
attending physician. A patient's risk of developing rabies must be carefully
considered before deciding to discontinue vaccination. Moreover, the use of
corticosteroids to treat life-threatening neuroparalytic reactions carries
the risk of inhibiting the development of active immunity to rabies. It is
especially important in these cases that the serum of the patient be tested
for rabies antibodies. Advice and assistance on the management of serious
adverse reactions in persons receiving rabies vaccines may be sought from the
state health department or CDC.

All serious systemic neuroparalytic or anaphylactic reactions to a rabies
vaccine should be immediately reported to the state health department or the
Division of Viral Diseases, Center for Infectious Diseases, CDC ({404}
329-3095 during working hours, or {404} 329-2888 at other times).

PRECAUTIONS AND CONTRAINDICATIONS

Immunosuppression

Corticosteroids, other immunosupressive agents, and immunosuppressive
illnesses can interfere with the development of active immunity and
predispose the patient to developing rabies. Immunosuppressive agents should
not be administered during postexposure therapy, unless essential for the
treatment of other conditions. When rabies postexposure prophylaxis is
administered to persons receiving steroids or other immunosuppressive
therapy, it is especially important that serum be tested for rabies antibody
to ensure that an adequate response has developed.

Pregnancy

Because of the potential consequences of inadequately treated rabies
exposure and limited data that indicate that fetal abnormalities have not
been associated with rabies vaccination, pregnancy is not considered a
contraindication to postexpsoure prophylaxis. If there is substantial risk of
exposure to rabies, preexposure prophylaxis may also be indicated during
pregnancy.

Allergies

Persons with histories of hypersensitivity should be given rabies
vaccines with caution. When a patient with a history suggesting hypersen-
sitivity to HDCV must be given that vaccine, antihistamines can be given;
epinephrine should be readily available to counteract anaphylactic reactions,
and the person should be carefully observed.

* If these are unavailable, call the Division of Viral Diseases, Center for
Infectious Diseases, CDC ({404} 329-3095 during working hours, or {404}
329-2888 nights, weekends, and holidays).

** Official name: Rabies Vaccine. The duck embryo vaccine which was used from
1957-1982 is no longer available in the United States.

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